Mortality
and Morbidity in Transsexual Patients With Cross-Gender Hormone Treatment

H.
Asscheman, L.J.G. Gooren, and P.L.E. Eklund

Sex steroid treatment is associated with side
effects. The number of deaths and morbidity cases in 425 transsexual
patients treated with cross- gender hormones were evaluated retrospectively
and compared with the expected number in a similar reference group of
the population. The number of deaths in male-to-female transsexuals
was five times the number expected, due to increased numbers of suicide
and death of unknown cause. Combined treatment with estrogen and cyproterone
acetate in 303 male-to-female transsexuals was associated with a 45-fold
increase of thromboembolic events, hyperprolactinemia (400-fold), depressive
mood changes (15-fold), and transient elevation of liver enzymes. Androgen
treatment in 122 female-to- male transsexuals was associated with weight
increase >10% (17.2%) and acne (12.3%). In both groups persistent
liver enzyme abnormalities could be attributed to other causes than
sex steroids (hepatitis B and alcohol abuse). Much of the morbidity
was minor and reversible with appropriate treatment or temporary discontinuation
of hormone treatment. Thus, the dilemma of prescribing cross gender
hormones in view of the needs of these patients is not resolved. Explanation
of possible side effects and careful clinical judgment remain the cornerstone
of the clinical decision to prescribe cross- gender hormones. Furthermore,
follow up of this relatively young population to disclose long-term
side effects and to elucidate the association of sex steroids with coronary
heart disease, as well as efforts to reduce the risk of thromboembolic
events, are required. Transsexual seek to adapt their bodies to the
opposite biologic sex to which they perceive themselves belonging. Hormonal
treatment plays an important role in this process.1 Ideally, the given
hormone treatment should suppress the secondary sex characteristics
of the original sex, as well as induce those of the opposite sex to
the fullest extent and in the shortest possible period of time. Therefore,
there is an inclination to maximize hormone dosage, which may involve
health hazards.

Side effects of sex steroid therapy in more conventional categories
of patients have been extensively reported: oral contraceptives in
women of reproductive age,2,3 estrogen substitution in postmenopausal
women,4-6 estrogen treatment of prostatic carcinoma,7 and androgen
replacement in men.8 Reports on side effects of cross-gender hormone
treatment in transsexuals have been few. One study evaluating the
efficacy of estrogens and androgens in 90 transsexual patients documented
only liver enzyme abnormalities and mild elevations of cholesterol
and triglyceride levels.9 Case reports have described pulmonary embolism,10
cerebral thrombosis,11 myocardial infarction,12 prostatic metaplasia,13
and breast cancer14,15 in estrogen- treated male-to-female transsexuals
and recurrent myocardial infarction in a female-to-male transsexual
treated with androgens.16 We report here a retrospective investigation
into the side effects of cross gender hormone administration in 425
transsexuals treated between 1972 and 1986.

MATERIALS AND METHODS
The files of all patients seen in our outpatient department between
1972 and 1986 were reviewed Diagnosis of transsexualism followed the
Standards of Care of the Harry Benjamin Gender Dysphoria Association.17
There were files of 558 patients with a problem of gender dysphoria,
of whom 425 were included in this study. Reasons for exclusion of
the others were as follows: no hormonal treatment (n = 71), only antiandrogen
treatment (n = 6), failure to comply with our follow-up schedule (n
= 15), no data available (n = 10), and treatment either not yet started
or for less than six months (n = 31). The population included in this
analysis comprised 303 male-to-female and 122 female-to-male transsexuals.
Our standard hormone treatment regimen in male- to-female transsexuals
consisted of 100 mg cyproterone acetate and 100 mg ethinylestradiol/
day orally (n = 258). Until 1980 diethylstilbestrol (5 to 15 mg/d)
was prescribed for a few patients. Some patients insisted on parenteral
estrogen therapy. They procured the estrogens outside our clinic and
these were self-administered in a dose of 200 to 800 mg estradiol-17-
undecanoate/month in (n = 45). Recommended dose of parenteral estrogens
in postmenopausal women is 20 to 100 mg/m.

The patients' ages at the start of hormone treatment ranged from 16
to 67 years (median 32 years) in male-to-female patients and 16-54
years (median 25.4 years) in female-to-male patients. The duration
of hormone therapy ranged from six months to more than 13 years (median
4.4 years in male-to- female and 3.6 years in female-to-male patients).
In the first two years of treatment, patients were seen every three
months and every six to nine months thereafter. At each visit physical
changes and complaints were recorded and a general physical examination
was carried out. At least once, and generally twice a year, blood
samples were drawn for determination of liver enzymes, prolactin levels,
and, if indicated, other laboratory parameters. Diagnosis of venous
thrombosis or pulmonary embolism was confirmed by phlebography or
lung scintigraphy. Twelve transsexuals died during this follow-up
period. The cause of death was determined either by autopsy report
or from information given by the patients's general practioner. The
expected mortality and morbidity of a comparable group of subjects
were calculated from published reports on the incidence of mortality
and similar morbidity in the general population aged 15 to 64 years.
The expected number of cases was adjusted for age (15-24, 25-39, and
40-64 years of age) and sex,18 as well as for the period of time the
study population was on cross-gender hormone treatment.

RESULTS
The observed and the expected mortalities in male to-female transsexuals
treated with estrogens and cyproterone acetate are shown in Table
1. The total number of deaths in the treatment group represented a
2.5- to 9-fold increase over the general population. The increased
mortality was in particular due to an increase of suicides and of
deaths by unknown cause. There may have been a connection to sex steroid
treatment in the three deaths of unknown cause, although autopsy in
two of these cases failed to demonstrate a hormone-related cause.
All other causes of death were within the 95% confidence intervals
of the expected mortality. As can be expected in a relatively young
age group, six of the 12 deaths (95% Cl, 2.5-9.5) were not from natural
causes.

A summary of all morbidity encountered and, if data were available,
the number of expected cases in the general population, aged 15 to
64 years, is shown in Table 2 (male-to-female transsexuals) and Table
3 (female-to-male transsexuals).

A clinically serious side effect of estrogen treatment (45-fold increase)
was venous thrombosis of the legs (n = 13) and/or pulmonary embolism
(n = 6). Of the total male to-female transsexual group this occurred
in 19 (6.3%) patients, yet was expected in only one patient. In the
235 male-to-female transsexuals who underwent sex reassignment surgery
4 (1.7%) were diagnosed postoperatively with venous thrombosis and/or
pulmonary embolism. This low postoperative incidence in comparison
to the total incidence of thromboembolic events in our patients is
probably due to our policy of discontinuing all hormone treatment
at least 4 weeks before surgery. If thrombosis attributed to estrogen
occurred, this happened most often during the first year of treatment
(ten of 13 cases). Furthermore, there was a strong association between
age and the incidence of thrombosis: five of 237 (2.1%) patients under
40 years of age v eight of 66 (12%) patients over 40 years (P <
.05, chi- square test). In the cases of thrombosis that occurred postoperatively
or following leg trauma (one severe leg contusion and one tibial fracture),
this association with age was not significant (2.2% v 4.0%), possibly
due to the low number of cases.

The two cases of myocardial infarction occurred, after several years
of hormone treatment, in one 45- and in one 50-year-old male-to-female
transsexual. Both had a strong positive family history of heart disease
and one also smoked 50 cigarettes a day.

Table 1. Observed Mortality in 303 Male-to-Female Transsexuals Treated
With Estrogens and Cyproterone Acetate, and Expected Mortality in
the General Male Population 15 to 64 Years of Age (Adjusted for Age
15 to 24, 25 to 39, end 40 to 64 Years)

Malady

No.
Observed (95% Cl)

No.
Expected

Suicide

3
(0.63-8.8)

0.208

Murder

1
(0.024-5.5)

0.022

Accidental
drowning

2

NA

Unknown
Causes

3
(0.63-8.8)

0.103

Myocardial
infarction

1
(0.024-5.5)

0.619

COPD

1
(0.024-5.5)

0.066

Pancreatitis

1
(0.024-5.5)

0.075

Total
number of deaths

12
(6.3-20.9)

2.333

Abbreviation:
NA, not available.

Table
2. Observed Morbidity in 303 Male-to-Female Transsexuals Treated With
Estrogens and Cyproterone Acetate and Expected Number of Cases in
the General Male Population 15 to 64 Years of Age (Adjusted for Age
15 to 24, 25 to 39, and 40 to 64 Years)

For
four patients with preexistent hypertension, kept adequately under
control through medication (<150/90 mmHg), hormonal therapy was
not considered to be contraindicated. Ten patients developed high
blood pressure (>160/95 mmHg) during sex steroid treatment. With
appropriate antihypertensive treatment we were able to manage this
without discontinuing the steroids. In the first six months of hormone
treatment depressive mood changes were reported spontaneously by 25
(8.3%) male-to-female patients. We did not specifically inquire into
depressive symptoms nor was psychometric testing done of these patients.
However, before the start of treatment all patients were informed
of the possible effects hormones could have on their mood.

Serum prolactin levels increased in all estrogen-treated patients.
In 46 (21.4%) patients serum prolactin levels rose to more than 1,000
mU/L (upper limit for males 300 mU/L), whereas only 0.108 of 214 patients
were expected according to published prevalence rates.19 After reduction
of the estrogen dosage serum prolactin levels fell to only slightly
elevated values in 23 patients. CT scanning of the pituitary with
contrast enhancement was performed in 15 of the 23 remaining patients
(eight were either lost for follow-up or they refused radiologic evaluation).
In five of these 15 patients pituitary enlargement was documented.20

In female-to-male patients androgen treatment deepened the voice,
increased body hair growth, and induced beard growth to a varying
extent. Shaving became necessary in >90% of them after one year
of androgen treatment and some grew a full beard. Severe acne was
observed in 15 (12.3%) subjects. Topical treatment for the acne was
moderately effective in most patients. All 21 patients (17.2%) who
gained more than 10% body weight were already obese before the start
of testosterone administration. Minor weight increase (I to 3 kg)
was common in both estrogen- and androgen-treated patients, but minor
weight loss was also regularly documented.

DISCUSSION
This study is a retrospective and not a case-control study. Therefore,
no definitive conclusions about the relative risks of cross-gender
hormone treatment can be drawn. The conclusion of this study could
have been more firm if a control group had been included. It did not
appear feasible to match our group, which was heterogeneous in age
and duration of hormone treatment, with a control group. In the latter
group there should have been a similar follow-up with regular clinic
visits and laboratory tests. To compensate for this drawback, we compared
our findings with the expected number of deaths and morbidity calculated
from health statics, adjusted for age and sex, of the general population.
This approach still poses a problem because our group was selected
in two ways: (1) in our clinical population serious preexistent morbidity
was excluded (eg, serious cardiovascular disease), and (2) the patients
were treated on the basis of their transsexualism, which might be
associated with a greater proneness to some pathologies (eg, suicide).
How ever, these comparisons are the best available for clinical evaluation
of cross-gender hormone treatment. Compliance with the prescribed
hormones was obvious from the induced physical changes and was not
monitored in this study.

The increased mortality in male-to-female transsexuals compared with
the expected mortality can be partly explained by the increased suicide
rate. Many patients (14%, unpublished observations of our group) attempted
suicide before the start of sex reassignment treatment. This increased
suicide rate confirms the notion that gender reassignment is not fully
effective in relieving co-existent morbidity in cases of gender dysphoria.
The increased number of deaths by unknown cause does raise concern.
Two of these three deaths might have been suicide, according to friends
and relatives. The autopsy of one did not include toxicologic screening;
thus, the assumption of suicide cannot be refuted. More extensive
follow-up will be necessary to evaluate the risk of death by unknown
cause.

In accordance with previous studies of hyperlipemic men treated with
estrogens,2l our study shows an increased incidence of thrombosis
in estrogen- treated male-to-female transsexuals. The observed incidence
in our study of 1,140 of 100,000 exposure years is similar to the
incidence of 1,100 of 100,000 exposure years calculated from the data
of the Coronary Drug Project Research Group.21 In comparison, the
incidence of thromboembolic disease in oral contraceptive users is
300 of 100,000 exposure years and in healthy men estimated at 30 of
100,000 exposure years.2 The magnitude of this increased incidence
rate of thromboembolic events is worrisome and should be a stimulant
for research for less thrombogenic hormone schedules. Either reduction
of the estrogen dosage to the lowest possible effective dose, similar
to what has been shown with oral contraceptives, or another way of
administering, eg, percutaneous estradiol with less hepatic effects,
might be effective ways of reducing this risk. We also found advanced
age (>40 years) to be a factor affecting the incidence of documented
venous thrombosis and pulmonary embolism in male to-female transsexuals
using estrogens. The latter results have also been reported in women
using oral contraceptives.3

The connection between sex hormone levels, coronary heart disease,
and coronary risk factors is complex.22 Epidemiologic studies suggest
that changes in blood lipid levels similar to those that occur during
estrogen treatment reduce the risk of coronary heart disease.23 Yet,
it has been found that estrogens did not prevent recurrent episodes
of clinical coronary heart disease in hyperlipemic men with previous
myocardial infarction.21 Furthermore, in prostatic cancer patients,
treatment with estrogens has been associated with an increased incidence
of cardiovascular events24 and mortality.25 Our follow-up study of
relatively young and healthy gender dysphoric males has still been
too short to confirm any association.

The effect of androgens on blood lipids (increasing total cholesterol
and decreasing HDL-cholesterol26 has also been found in women treated
with testosterone cypionate (100 to 800 mg/mo im) for transsexualism.9
In this cross-sectional study these authors reported an increase of
the total cholesterol levels in the low (100 to 300 mg/mo) and high
dosage (800 mg/mo) regimen (11 observations) and no increase in the
medium dosage of 400 mg (30 observations). This last dosage is comparable
to the dosage we used. Our limited number of prospective observations,
as yet insufficient for statistical analysis, shows a highly variable
response. Theoretically, the increased serum total cholesterol and
decreased HDL-cholesterol level could increase the risk of coronary
heart disease. To our knowledge, only one case report supports this
assumption, although pretreatment serum lipid levels in this case
were not available.16 The relatively young age and the follow-up period
of median 3.6 years in our study preclude a definite conclusion.

The number of cases of hypertension observed is slightly less than
expected. This observation is in contrast with the reported effect
of oral contraceptives on blood pressure in women.2 Meyer et al9 also
failed to find changes of arterial blood pressure in estrogen-treated
male-to-female transsexuals. This discrepancy with the findings in
oral contraceptive users may be explained by the way blood pressure
readings were made. In their study and in the present study blood
pressure was measured during clinic visits in patients who often came
for the first time to a gender clinic. Blood pressure readings in
this setting tend to be higher because of the nervous stress associated
with new experiences. At follow-up visits the blood pressure decreases
and can mask the increase caused by estrogens. Another reason we did
not observe more cases of hypertension in the study group may be the
relatively high prevalence of hypertension in the Dutch male population
aged 15 to 49 years.27 This could obscure an increased incidence associated
with estrogen and/or cyproterone acetate. More recent studies on blood
pressure in women taking estrogens as replacement treatment also contradict
the general assumption that estrogen treatment is associated with
an increase in blood pressure. Actually, the majority of women in
these studies experienced a decline in blood pressure.28,29

Temporary mood changes were spontaneously reported by a considerable
number of male-to-female transsexual patients in the first six months
of treatment but subsequently waned. In particular, cyproterone acetate
has been reported to be associated with a lack of energy and depressive
mood changes.30 The reason for these mental changes may not only be
the hormone effect but also the psychologic pressure of living in
the new gender role. Because depressive mood changes were found predominantly
in the first six months of the hormone treatment, it is improbable
that there has been an association with the three observed suicides:
they occurred after 1.5, 4, and 8 years of hormone treatment.

If liver enzyme abnormalities were observed, patients were examined
by hepatitis serology, ultrasonography of the liver, and follow-up
of liver enzyme tests, in particular, if applicable after discontinuation
of alcohol abuse. Most persistent liver enzyme abnormalities could
be attributed to hepatitis B and alcohol abuse. No evidence of liver
tumors, such as peliosis hepatis or hepatic adenoma, was observed.
Transient liver enzyme abnormalities, similar to those found in the
present study, have also been observed in estrogen-treated prostatic
cancer patients but did not result in liver damage.31

The other side effects of cross-gender hormone treatment were minor.
Many side effects were reversible with appropriate therapy or temporary
discontinuation of hormones. The occurrence of serious side effects
(eg, the prevalence of thromboembolic disease of 6.3%) was, however,
not rare. In view of the needs of transsexuals these side effects
present a difficult dilemma in hormonal gender reassignment. At present
no firm guidelines can be given. The cornerstone of the decision to
prescribe cross-gender hormones remains with the explanation of the
possible side effects to the patients and careful clinical judgment.
Further follow-up of this relatively young population to disclose
long-term side effects and to elucidate the association of sex steroids
with coronary heart disease, as well as efforts to reduce the risk
of thromboembolic events, are required.

ACKNOWLEDGMENT
The authors thank Jos Megens for his invaluable administrative and
organizational contributions to this study, Elisabeth Savage, MA,
and Dr Keith Courtney for their editorial assistance, and Dr Jos Nauta
for his statistical advice.

13.
Goodwin GE, Commings RH: Squamous metaplasia of the verumontaniem
with obstruction due to hypertrophy: Long-term effects of estrogen
on the prostate in an aging male to female transsexual. J Urol 131:553-554,1984

32.
Hoogendoorn D: Atherosclerotic diseases of the heart and in the statistics
of causes of deaths. Ned Tijdschr Geneeskd 129: 1827-1833, 1985

33.
Hoogendoorn D: Atherosclerotic diseases of the brain as seen in hospitals
and in the national statistics of causes of death; the cerebrovascular
accident (CVA). Ned Tijdschr Geneeskd 129: 1883-1887, 1985